Alkoxy-substituted-n lower alkanoyl
morpiiinans



- 3,201,403 Patented Aug. 17, 1965 United States Patent Ofice 3,201,403 3 ALKOXY-SUBSTITUTED-N LOWER ALKANOYL MORPHINANS Yoshiro Sawa, Hyogo Prefecture, and Naoki Tsuzi and Haruhiko Tada, Osaka Prefecture, Japan, assignors to Shionogi & Co., Ltd., Osaka, Japan No Drawing. Filed Apr. 3, 1963, Ser. No. 270,186 Claims priority, application Japan, Apr. 6, 1962,

7 Claims. ((11. 260-285) I The present inventionrelatesto and production thereof. I T

In the'term morphinan" herein employed, there are included all the compounds having the fundamental structure representable by the following plane formula:

wherein R represents a lower alkyl group (e.g., methyl, ethyl, propyl), R'- represents-a hydrogen atom, an aryloxy group (e.g., phenyloxy, naphthyloxy) or a substituted arylo'xy group (e.g., substituted phenyloxy, substituted naphthyloxy) wherein the substituent is lower alkyl (e.g., methyl, ethyl, propyl), lower alkoxy (e;g., methoxy, ethoxy, propoxy), nitro or amino, R" andRf" each represents a methylene group, a hydroxymethylene group; a carbonyl groupor a ketalated carbonyl group (e.g., ethylmorphinan derivatives I enedioxymethylene, diethoxymethylene), X represents a hydrogen atom or a hydroxyl group and Y represents a lower alkyl group (e.g., methyl, ethyl, propyl), an aryl group (e.g., phenyl, naphthyl) or an ar(lower)alkyl group (e.g., benzyl, phenethyl) and shows various pharmacological activities such as analgesic activity, antitussive activity and antiinfiammatory activity.

Accordingly, a basic object of the present invention is to embody the morphinan derivative of Formula I. Another object of the invention is to embody the pharmacologically active'Nesubstituted morphinan (I). A further object of the invention is to embody a process for preparing the N-substituted morphinan (I). 1 These and other objects will be apparent to those conversant'with the art to which the present invention pertains from the subsequent description.

The process of the present invention is illustratively represented by the following scheme:

-cH,-Y l, RI

wherein R, R, R", R', X and'Y each has the same significance as designated above.

As the starting material, there may be used the optically active or racemic morphinan of Formula II.

According to the process of the present invention, the startingmorphinan (II) is subjected to acylation, followed by reduction of the resultant N-acylmorphinan (III) to the objective N-substituted morphinan (I). The acylation can be accomplished by treating the morphinan (II) with a conventional acylat-ing agent represented by the formula: Z-CO-Y wherein Y has the same significance as designated above and Z represents a reactive residue of the functional acid derivatives, preferably acid anhydride (e.g.,

acetic anhydride, propionic anhydride, butyric anhydride) or acid halide (e.g., acetyl chloride, propionyl chloride, butyryl chloride, benzoyl chloride, naphthoyl chloride,

phenacctyl chloride, phenacetyl bromide) at a temperature from room temperature (15 to 30 C.) to reflux temperature. If necessary, aninert organic solvent (e.g., benzene, toluene, acetone, dioxane, tetrahydrofuran) may be used as the reaction medium. The addition of an inorganic or organic base (e.g., sodium carbonate, potassium carbonate, pyridine,,picoline, dimcthylaniline) as a condensing agent may afford good results. In the acylation reaction, any group which can react with the said acylating agent as the l4-hydroxyl group may be simultaneously acylated.

However, the intended N-acylation is not blocked by this side reaction. The subsequent reduction can be effected by treating the resulting N-acylmorphinan (III) with a metallic hydride complex (e.g., lithium aluminum hydride, sodium borohydride) in an inert solvent medium. The solvent may be properly selected depending on the property of the N-acylmorphinan' (III) and the reducing agent. Illustrative solvents include water, methanol, ethanol, ether, tetrahydrofuran and dioxane. The reaction can proceed at room temperature (15 to 30 C.). but heating so as to reflux is usually preferred. In the reduction reaction, any reducible group as the 6-oxo group may be simultaneously reduced. However, the intended reduction of the carbonyl group in the N-acyl group is not inhibited by this side reaction. Moreover, the reducible group may be previously protected in a per se conventional manner, when the simultaneous reduction of the same is unfavorable.

The objective N-substituted morphinan (I) occurs in optically active form as well as in racemic mixture and these are all within the scope of the present invention.

The N-substituted morphinan (I) forms acid addition salts with organic and inorganic acids. Illustrative acid addition salts include the hydrohalide (e.g., hydrochloride,

No'ri-z.'lhc rtntitussive activity was observed by the Winter method [Winter ct al. J. I'Jxpcr. Mcd., vol. 101, p. 17 (1955)] in gnincn pigs and is shown as the effective ratio to codeine, the value of which is expressed as 1. The toxicity was tested by the intravenous administration of the tested compound to mice and is shown by llDm (lethal dose).

Accordingly, they are useful as analgesic, antitussive and/ or antiinflammatory agents.

Practical and presently preferred embodiments of the present invention are illustrated by the following examples. In the examples, abbreviations eachhave conventional meanings, e.g. mg.=milligram(s), g.=gram(s), mi.=mi-llilitre(s), C.'=degrees centigrade.

Example 1 Preparation of (+)-3-methoxy-4-phenyloxy-N-ethylmorphinan (cis):

COCH g 3 N cra e hydrobromide, hydroiodide), sulfate, phosphate, nitrate, tartrate, salieylate, benzoate, malate, citrate, acetate, etc.

The thus-produced N-substituted morphinan (I) and acid addition salts thereof exhibit various pharmacological activities such as analgesic activity, antitussive activity and antiinfiammatory activity. For instance, the analgesic activity and the toxicity of some N-substituted morphinans according to the present invention are shown in the following Table I;

NUTl-Z.---Tli0 analgesic activity was observed by the Hniincr- IIcssc method iilesse: Arch. exp. Path. 11, PlliliiiL, vol. 155. p. 2-i3 (1030) in mice and the iYAmonr-Smith method [1) Amour et at. J. IharmucoL, vol. 1, p. 255 (1040)] in rats and is shown us the effective ratio to morphine, the value of which is expressed as 1. The toxicity was tested by the intravenous iuiininistmtion ot the tested compound to mice and is shown by LDm (lethal dose),

Further, for instance, the antitussive activity and the toxicity of some N-substituted morphinans according to the present invention are shown in the following Table II:

A solution of (+)-3-methoxy-4-phenyloxymorphinan (cis) (0.94 g.) in acetic anhydride (2 ml.) is heated on a water bath for 15 minutes and then acetic anhydride removed by distillation. The residue is mixed with water and shaken with ether. The ether extract is chromatographed on alumina to eliminate impurities, The resultant ether solution is evaporated to give (+)-3- methoxy-4-phenyloxy-N-acetylmorphinan (cis) (0.92 g.) as an oil.

A solution of (+)-3-methoxy-4-phenyloxy-N-acetylmorphinan (cis) (2.0 g.) prepared above in anhydrous ether (50 ml.) is dropwise added to a solution of lithium aluminum hydride (0.78 g.) in anhydrous ether (500 ml.) while stirring. The resultant mixture is refluxed for 5 hours while stirring. After decomposition of excess of lithium aluminum hydride with water, the ether layer is separated and shaken with dilute hydrochloric acid. The hydrochloric acid layer is made to alkalinity with sodium hydroxide and shaken with ether. The ether layer is separated and chrom-atographed on alumina to eliminate impurities. The resulting ether solution is evaporated to give (+)-3-methoxy-4-phenyloxy-N-ethylmorphinan (cis) (1.71 g.) as an oil, The oil is treated with hydrobromic acid and crystallized from water to give (+)-3-methoxy- 4-phenyloxy-N-ethyimorphinan (cis) hydrobromide as crystals melting at 257 to 260 C. (decomp). [c1 +7.2 (ethanol).

Analysis-4211M. for C l-l O NHBnH Oz, C, 63.02; H, 7.19; 'N, 2.94; Br, 16.77. Found: C, 62.73; H, 7.42; N, 2.94; Br, 16.83.

The starting material of this example, (+)-3-mcthoxyzene (10 ml.) is refluxed for 1.5 hours,

4-plhenyloxymorphinan (cis), IS

the following scheme:

Preparation of (+)-3-methoxy-4-phenyloxy-N-phenethylmorphinan (cis):

prepared "from (+)-3- methoxy-4-phenyloxy-N-methylmorphinan (cis) [Sawa et al.: Tetrahedron, vol. 15, p. 144 (1961)] according to 6, A solution of (+)-3-methoxyA-phenyloxy-N-phenacetyl-morphinan (cis) (1.4 g.) prepared above in anhydrous ether (40 ml.) is dropwise added to a solution of lithium aluminum hydride (0.31 g.) in anhydrous ether (30 ml.) and the resultant mixture is refluxed for 5 hours.- After decomposition of excess of lithium aluminum hydride with water, the ether layer is separated and shaken cH o c150 C6H50 0 1x 0 I N N-COCH2C6H5 A solution of (+)-3-methoxy-4-phenyloxymorphinan (cis) (1.7 g.) and phen-acetyl chloride (1.2 ml.) in ben- The reaction mixture is washed with water, dilute hydrochloric acid and aqueous sodium hydroxide and chromatographed on alumina to eliminate impurities. The resultant benzene solution 'is evaporated to give (+)-3-methoxy-4-phenyloxy-N phenacetylmorphinan (cis) (2.0 g.) as an oil.

7 Analysis.-Calcd. for C H O N: C, 82.08; H, 7.78; N, 3.09. Found: C, 81.67; H, 8.01; N, 3.17.

Example 3 8 ing at 225 to 227 C. (decomp.). [a] "+3l.9 (ethanol).

AnaIysis.Calcd. for C H ONJ-IBLH O: C, 59.37;

Preparation of (+)-3-meth0xy-N-ethy1morphinan H, Found: (cis): 5 The starting material of this example, (+)-3-meth0xy- (ll-I30 I OH o go 3 I F-CH CII.

A solution of (+)-3-rnethoxymorphinan (cis) (2.85 g.) in acetic anhydride (1.5 ml.) is heated on a water bath for 1 hour. The reaction mixture is combined with water and acetic acid removed by distillation. The resulting substance is dissolved in benzene, washed with aqueous sodium hydroxide, dilute hydrochloric acid and water in order and the solvent removed to give (+)-3- methoxy-6-acetylmorphinan (cis) (3.06 g.) as an oil.

The ether layer is separated and chromatographed on alu-;

mina to eliminate impurities. The resulting ether solution is evaporated to give (+)-3-methoxy-N-ethylmorphinan (cis) (2.64 g.), which is treated with hydrobromic acid and crystallized from water to give )-3-methoxy- N-ethylmorphinan (cis) hydrobromide as crystals melt- )-3-methoxy-N-acetylmorphinan morphinan (cis), is prepared from (+)-3-methoxy-4- phenyloxy-morphinan (cis) [cf. Example 1 of this specification] according to the following scheme:

(ll I Treatment with. metallic sodium -in liquid ammonia.

Example 4 Preparation of (+)-3-methoxy-N-phenethylmorphinan (cis):

NH -00CH2C6H5 ca o -crr ca c rr A solution of (+)-3-methoxymorphinan (cis) (4.15 g.) and phenacetyl chloride (2.5 ml.) in benzene ml.) is refluxed on a water bath for 1.5 hours. The reaction mixture is washed with water, dilute hydrochloric acid and aqueous sodium hydroxide in order and chromatographed on alumina to eliminate impurities. The resultant benzene solution is evaporated to give (+)-3-methoxy-N-phenacetylmorphinan (cis) (4.87) g. as an oil.

A solution of (+)-3-methoxy-N-phenaoetylmorphinan (cis) (4.87 g.) prepared above in anhydrous ether ml.) is dropwise added to a solution of lithium aluminum hydride (1.95 g.) in anhydrous ether ml.), and the resultant mixture is refluxed for 5 hours. After decomposition of excess of lithium aluminum hydride with I v 9 i l I w v water, the ether layer is separated and shaken with dilute an oil. The oil is treated with hydrobromic acid and hydrochloric acid. The hydrochloric acid layer is made crystallized from water to give ()-3-met.hoxy-N-ethylto alkalinity with sodium hydroxide and shaken with .morphinan (cis) hydrobromide as crystals meltingat 244 ether. The ether layer is separated and chromatographed to 258 C. [a] -29.3 (ethanol). onalumina to eliminate impurities. The resulting ether The starting material of this example, ()-3-methoxy solution is evaporated to give (+)-3-methoxy-N-phen- N-ethylmorphinan (cis), is prepared from ()-3-me- (decompi). [011 +S9.l'(ethanol).

ethylmorphinan (cis) (4.14 g.) as an oil. The oil is thoxy-N-methylmorphinan (cis) [Sawa et al. [Tetratreated with oxalic acid and crystallized from hydrous hedron, vol. 15, p. 154 (1961)] according to thefollowethanol to give (+)-3-methoxy-N-phetiethylmorphinan ing scheme:

CH O CH O Reflux with cyanogen bromide in chloroform.

Ill-CH3 N-CN Reflux with hydrochloric 1 acid. a NH (cis) oxalate as crystals melting at 2 04 'to 205 C. Exa p 6 I Preparation of (-)-3-methoxy-N-phenethyhnorphinan Analysis.-Calcd. for C H ON.(COOH) /2H O: C, (cis):

CH v i l i l N-CH CH 0 N-COCH2C6H5 z 2 6H5 70.41; H, 7.44; N, 3.04. Found: C, 70.70; H, 7.33; N, Example Preparation of -3 -meth0Xy-Nethylmorphinan (1.8 ml.), and the resultant solution is refluxed for 3 To a solution of (--)-3-methoxymorphinan (cis) (2.97

To a solution of (-)-3 methoxymorphinan (cis) (3.28 60 hours. The reaction mixture is washed with water, dilute g.) in benzene ml.), there is added acetic anhydride hydrochloric acid and aqueous sodium hydroxide in order, (1.7 ml.), and the resultant solution is refluxed for 1 dried and evaporated to give (-)-3 methoxy-N-phenacehour. After removal of the solvent, the residue is distylmorphinan (cis) (4.08 g.) as an oil.

solved in benzene, washed with dilute hydrochloric acid A solution of ()-3-methoxy-N-phenacetylmorphinan g.) in benzene ml.), there is added phenacetyl chloride and aqueous sodium carbonate in order and evaporated to (cis) (4.08 g.) above prepared in anhydrous ether (80 give (-)-3-methoxWN-acetylmorphinan' (cis) (3.67 g.) ml.) is dropwise added to a suspension of lithium aluas an oil. minum hydride (1.6 g.) in anhydrous ether (80 ml.) in

A solution of (-)-3-methoxy-N-acetylmorphinan (cis) about 20 minutes, and the resultant mixture is refluxed for (3.67 g.) prepared above in anhydrous ether (80 ml.) is 5 hours. After decomposition of excess of lithium aludropwise added to a solution of lithium aluminum hydride minum hydride with aqueous sodium hydroxide, the ether (1.86 .g.) in anhydrous ether (80 ml.), and the resultant layer is separated and evaporated to give (-)-3-methoxysolution is refluxed for 5 hours. After decomposition of N-phenethylmorphinan (cis) (3.64 g.) as an oil. The oil excess of lithium aluminum hydride with aqueous sodium is treated with tartric acid and crystallized from a mixture hydroxide, the ether layer is separated and evaporated to of isopropanol and water to give (-)-3-methoxy-N-phengive ()-3-methoxy-N ethylmorphinan (cis) (3.25 g.) as ethylmorphinan (cis) tartrate as crystals melting at 118 11 to 124 C. (decomp.) lai -36.5 (methanol). Analysis.-Calcd. for C H ON.C H O .2H O: C, 63.60; H, 7.55; N, 2.56. Found: C, 63.30; H, 7.51; N, 2.62.

Example 7 The above prepared (-)-3-methoxy-6,6-ethylenedioxyl4-hydroxy-N-acetylmorphinan (cis) (600 mg.) is combined with tetrahydrofuran (70 ml.) and lithium aluminum hydride (500 mg.) and stirred for 6 hours at room temperature (15 to 30 C.) The reaction mixture is 5 treated in a per se conventional recovery procedure and g gg igggg f g 3 methoxy 6 0x014 hydroxy N crystallized from ethanol to give ()-3-methoxy-6,6-

CH O

3 CH O OH NH N COCH3 it-coen ca o CH O N--CH CH O K o 0 A solution of (-)-3-methoxy 6 oxo l4 hydroxymorphinan (cis) (200 mg.) in acetic anhydride (2 ml.) is allowed to stand at room temperature (15 to 30 C.) overnight. The reaction mixture is treated in a per se conventional recovery procedure whereby the crude acetylated product (240 mg.) is obtained. The crude acetylated product is chromatographed on alumina (4 g.). The eluates with benzene chloroform (1:1) and dichloromethane are combined together and crystallized from ethanol to give (-)-3-methoxy-6-oxo-14-hydroxy-N-acetylmorphinan (cis) (124 mg.) as crystals melting at 196 to 197 C. [oz] 187 (chloroform),

Analysis.-Calcd. for C H NO C, 69.28; H, 7.04; N, 4.25. Found: C, 69.54; H, 7.18; N, 4.19.

The above prepared (-)-3-methoxy-6-oxo-l4-hydroxy N-acetylmorphinan (cis) -is subjected to ketalation in a ,per se conventional manner, i.e., the treatment with p-toluenesulfonic acid and ethylene glycol in benzene, to

give 3 methoxy-6,6-ethylenedioxy-14-hydroxy-N- acetylmorphinan (cis) (M.P-. 257 to 258 C.) in a yield of 95%.

ethylenedioxy-l4-hydroxy-N-ethylmorphinan (cis) (535 mg.) as crystals melting at 139.5 to 140.5 C. [111 70.0 (chloroform).

Analysis.Calcd. for C H NO C, 70.17; H, 8.13; N, 3.90. Found: C, 69.82; H, 8.16; N, 3.71.

The above prepared (-)-3-methoxy-6,6-ethylenedioxy- 14-hydroxy-N-ethylmorphinan (cis) (440mg) is combined with N hydrochloric acid (5 ml.) and heated on a water bath for 10 minutes. The reaction mixture is neutralizled with ammonia water and shaken with dichloromethane. The dichloromethane extract is evaporated and crystallized from ethanol to give ()-3-methoxy-6-oxo- 14-hydroxy-N-ethylmorphinan (cis) (380 mg.) as crystals melting, at 188.5 to 189.5 C. [a] 116.0 (chloroform). i

The starting material "of this example, ()-3-methoxy- 6-oxo-l4-hydroxymorphinan (cis), is prepared from ()-3-methoxy-4,14 dihydroxy-6-oxo-N-methylmorphinan [Speyer et al.: Ann., vol. 430, p. 1 (1923)] according to the following scheme:

CH O

C H O Heating with bromobenzene in the pre- Reflux with ethylene glycol and p-toluenesence of copper and potassium carbonat e a N-CH Treatment with metallic sodium ,x Ql I A @11 0 CH Y 3 v Reflux with 7 on i 113E110 acid a I N CH 0 J L f 1' 3 N-QH T v 011 0 Reflux with Reflux with cyanogen bromide hydrochloric in chloroform. E acid.

b V CF 0 l NH l j 0 e e What is claimed is: References Cited by the Examiner 1. 3-lower alkoxy-4-phenyloxy lower alkanoyl- UNITED STATES PATENTS morphinm 2 885 401 5/59 Grussner et al. 260-285 (+)-3- y -p y y N aceiylmorphman 308509l 4/63 Saw et aL (cis).

3. 3-1ower alkoxy-N-lower.alkanoylmorphinan. R N P TENTS 4, (+)-3-methoxy-N-acetylmorphinan (cis). 765,920 1/57 Great Britain. 5. ()-3-methoxy-N-aeetylmorphinan (cis). OTHER REFERENCES 6. 3-1ower alkoxy-6oxo-14-hydroxy-N-lower alkanoyl- '40 Hammg Ind and Eng Chem vol 37 pages 12647 morphinan. U945) 7. ()-3-methoxy-6-oxo-14-hydroxy N acetylmorphinan (eis). NICHOLAS S. RIZZO, Primary Examiner. 

1. 3-LOWER ALKOXY-4-PHENYLOXY - N - LOWER ALKANOYLMORPHINAN.
 6. 3-LOWER ALKOXY-6-OXO-14-HYDROXY-N-LOWER ALKANOYLMORPHINAN. 